In general, any process of pathological crystallisation is a consequence of an imbalance between three groups of factors: supersaturation, crystallisation promoters (basically heterogeneous nucleants) and repressors of crystallisation (crystallisation inhibitors and cellular defence mechanisms).
A system is supersaturated in relation to a solute when it contains it in amounts exceeding the amount established by its solubility product. It is thus a thermodynamic factor and is only a kinetic question (i.e. of the time elapsed) that the corresponding solid will be finally formed.
The promoters or heterogeneous nucleants are substances that facilitate the formation of the crystal, reducing the induction period by preventing the stage of homogeneous nucleation. These are thus kinetic factors.
The inhibitors of crystallisation are substances that hinder or prevent the development of crystals. They can act at the nucleation level (by adsorbing on the homogeneous or heterogeneous nucleus being formed), of crystalline growth (by adsorbing on the faces of the crystal being formed) or of both processes at once. It therefore also includes kinetic factors.
Myo-inositol hexaphosphate (phytate) is the most powerful inhibitor known of the development of calcium salts, and acts on the heterogeneous nucleation of the calcium oxalate, on the crystalline growth of the calcium oxalate and on homogeneous and heterogeneous nucleation of calcium phosphate. The phytate, together with the pyrophosphate, shows inhibitory effects both on the crystallisation of brushite and crystallisation of hydroxyapatite. Both compounds constitute two of the forms in which the calcium phosphate can crystallise, this last being a majority component of pathological vascular mineralisations.
It has been shown recently that phytate is present in all the organs, tissues and biological fluids of mammals, the human being among them. It has further been shown that most extracellular phytate found in organs, tissues and fluids of mammals has a dietary origin and is not the result of endogenous synthesis, whereas intracellular phytate (found in very much lower concentrations) is probably produced inside the cell. Its levels in the organism are therefore directly related to the exogenous supply thereof, either through dietary ingestion or topical application.
Blood plasma is always supersaturated in relation to calcium phosphate, due to the concentration values of phosphate, calcium and its pH. Indeed, calcifications are frequently found in the cardiovascular system, reducing the flexibility of the blood vessels and promoting thrombosis and arterial rupture. When such calcifications appear in the cardiac valves, they are associated with various disorders which, if not corrected, can lead to heart failure and death.
Various risk factors are now known that are associated with the development of calcifications in the coronary arteries, such as kidney disease, advanced age, high plasma cholesterol levels (a decrease in the cholesterol associated with high-density lipoproteins and increase in the cholesterol associated with low-density lipoproteins), obesity and high triglyceride levels, cytotoxic agents (smoking habit) and bacterial infections.
It must be born in mind that the occurrence of cardiovascular calcifications can start by as early as the second decade of life, and that coronary calcifications affect 50% of people aged between 40 and 49 years, and 80% of people aged between 60 and 69 years.
The precise mechanism of formation of a vascular calcification involves various steps, although in general it requires the prior existence of an injury which acts as an inducer (heterogeneous nucleant) of the calcification (calcium phosphate, generally in the form of hydroxyapatite). Subsequent development of the calcification will depend on the balance of the remaining factors (supersaturation, crystallisation inhibitors, cellular modulators of the calcification).
An important factor in preventing the development of cardiovascular calcifications is therefore the presence of crystallisation inhibitors. A recent document showed the preventive action of phytate on the development of cardiovascular calcifications when the phytate is applied topically (see PCT/IB2004/003588).
In a different field, hydroxyapatite is also accumulated in the buccal cavity through mineralisation of the dental bacterial plaque. Dental bacterial plaque is a deposit on the teeth that cannot be removed with water under pressure or simply by rinsing out the mouth. Brushing does help to prevent a speedy accumulation of such deposits, but even a regular brushing is not enough to remove all the deposits that adhere to the teeth. The plaque that adheres to the surface of the tooth can calcify (calcified dental plaque) to form dental tartar or calculus. The plaque is therefore a precursor of calculus. Unlike the calculus, however, the plaque can be formed on any part of the surface of the tooth, particularly on the gingival margin. Therefore the presence of plaque on the teeth, in addition to being unsightly, can be a precursor to the development of gingivitis and periodontal diseases. There is a direct correlation between the amount of bacterial plaque and the severity of the gingivitis.
The tartar or calculus are calcified deposits on the teeth which are formed due to mineralisation of the plaque, a process that starts within a period of 24-72 hours and takes an average of 12 days to reach maturity. It is made up of organic and inorganic matter with a composition very similar to that of other pathological calcifications observed in the organism (renal lithiasis, calcinosis cutis, etc.):                Organic matter: it mainly comes from microorganisms (bacteria, fungi, etc.) that are connected to one another, forming colonies, although it can also come from food debris remaining in the buccal cavity.        Inorganic matter: it is largely made up of calcium and orthophosphate present in the saliva which are arranged in a crystalline lattice called hydroxyapatite (HAP).        
The formation of calculi takes place in two steps. In the first one, the bacterial plaque is deposited on the teeth, being made up of living and dead bacteria surrounded by a gellified matrix derived from bacteria and saliva. In the second step, said plaque undergoes a process of mineralisation until forming the dental calculus. Initially, amorphous calcium phosphate begins to be deposited on and within the extracellular matrix of the dental plaque, which becomes sufficiently packed for the aggregates to be resistant to deformation, in the end turning into the crystalline HAP material. The amorphous calcium phosphate, though related to the HAP, differs from it in its crystalline structure, particle morphology and stoichiometry.
The inhibition of HAP formation has been tested by means of the action of inhibitors, sequestrants, efficient suppressors of calcium and magnesium ions and/or chelating agents. Dehydrated polyphosphates such as water-soluble hexametaphosphates, tripolyphosphates, pyrophosphates and the like have been used for this purpose.
We thus find a list of patents (U.S. Pat. No. 3,488,419; U.S. Pat. No. 4,215,105; U.S. Pat. No. 4,515,772) which utilise or make reference to the use and functions of these polyphosphates proposed to date in oral compositions. However, as disclosed in U.S. Pat. No. 4,627,977, the straight-chain dehydrated polyphosphates are hydrolysed significantly in the oral cavity and/or in the saliva by means of the enzymes in the saliva (phosphatases) into orthophosphates, which do not show any inhibitory action on the formation of HAP; although said hydrolysis is reduced through the combined use of these polyphosphates with fluoride (as disclosed in U.S. Pat. No. 4,808,4109) as well as with the fluoride ion forming part of a polocarboxylate polymer in the document U.S. Pat. No. 4,627,977, an efficient treatment inhibiting hydroxyapatite has yet to be found.
On the other hand, U.S. Pat. No. 5,300,289 describes antimicrobial oral compositions with phytate for mouth care. The oral compositions described contain phytic acid or pharmaceutically acceptable salt thereof, a cationic antimicrobial compound and compatibilizing agent for the control of the dental calculus, dental plaque, gingivitis, periodontitis and/or bad breath. In particular, it describes a composition comprising: (1) from 0.001 to 10% by weight of one or more compounds having C—O—P bonds, where the compound having the C—O—P bond is myo-inositol hexakis (dihydrogen phosphate), myo-inositol pentakis (dihydrogen phosphate), myo-inositol tetrakis(dihydrogen phosphate) or a physiologically acceptable salt thereof; (2) 0.001 to 10% by weight of one or more cationic antimicrobial compounds; and (3) 0.1 to 20% by weight of one or more compatibilizing agents. As a cationic antimicrobial compound a list of 10 possible compounds or derivatives thereof is disclosed. The compatibilizing agents are chosen from acids and their alkaline metal salts or alkaline earth metal salts, or mixtures thereof. It is also disclosed that the presence of a metallic ion selected from strontium, magnesium, tin, zinc, calcium or mixtures thereof in the aforesaid composition does not lead to precipitation of the phytic acid of the composition in solution and, therefore, the addition thereof to the above composition will help to suppress bad breath. The molar ratio between said metallic ion and the phytic acid can be present in an oral composition from 4:1 to 1:4, preferably from 3:1 to 1:3 and still more preferably, in a 1:1 ratio.
Furthermore, phytate has indeed already been used in oral compositions. Thus, in U.S. Pat. No. 4,259,316 and U.S. Pat. No. 4,335,102 the phytate is used in combination with a compound of tin (II). However, the formation of complexes between phytate and tin are not effective in inhibiting the formation of calculus.
Also, in U.S. Pat. No. 3,934,002, phytate is used in conjunction with a bisbiguanide as an antiplaque and anticaries agent. However, the two compounds react with each other so they cannot be distributed homogeneously throughout the oral composition, to the point that they even form two clearly visible phases.
A large number of compositions have been developed comprising different combinations of antiplaque and antigingivitis agents, together with or optionally together with other compounds such as for example anticalculus agents whose purpose is to eliminate the bacterial etiology and risk factors.
However, there does not yet exist a suitable treatment which permits the inhibition of the crystallisation of hydroxyapatite with good results.